A phase II study of lenvatinib plus pembrolizumab in patients with progressive, recurrent/metastatic adenoid cystic carcinoma.
Authors: Maliheh Mohamadpour, Eric Jeffrey Sherman, Anuja Kriplani, James Vincent Fetten, Lara Dunn, Loren S. Michel, Kin Wai (Tony) Hung, Shrujal S. Baxi, Erin McDonald, Rachel Conybeare, Nora Katabi, Irina Ostrovnaya, David G. Pfister, Alan Loh Ho
Journal: Journal of Clinical Oncology (2023)

6048 Background: Recurrent/metastatic adenoid cystic carcinoma (R/M ACC) is a rare salivary gland cancer (SGC) without standard treatments. The multitargeted, antiangiogenic kinase inhibitor lenvatinib (len) has activity in R/M ACC, but immune checkpoint inhibitor (ICI) therapies lack efficacy. Hypothesizing that VEGFR inhibition can enhance ICI-induced responses, we conducted a phase II trial evaluating len plus the programmed death-1 (PD-1) inhibitor pembrolizumab (pem) in two R/M SGC cohorts: ACC and non-ACC. Here we report results from the completed ACC cohort. Methods: Patients (Pts) with R/M ACC were enrolled. RECIST v1.1 measurable disease and evidence of progression on imaging performed within 6 months of enrollment were required; any number of prior therapies was allowed. Pts were treated with len 20 mg orally daily and pem 200 mg intravenously every 3 weeks (21-day cycles). The primary objective was to evaluate best overall response rate (ORR), seeking an ORR improvement with len+pem from 15% (previously reported with len alone) to 35%. In the first stage, &gt; 3 confirmed complete and partial responses (cCRs+ cPRs) were required among 17 pts to continue to the second stage; &gt; 8 responses among 32 total pts would have been considered positive (1-sided alpha 0.1, power 0.9). Secondary objectives included evaluating progression-free survival (PFS) and safety/tolerability per CTCAE v5.0 criteria. Results: 17 R/M ACC pts were enrolled and evaluable for the primary objective. One pt had a cPR for an ORR of 6%, failing to meet the rule for progression to the second stage. Thirteen (76%) pts had stable disease and 2 (12%) progression of disease as best response; 1 pt did not have response assessed. Thirteen (76%) pts experienced some degree of regression in RECIST target lesions (TLs; -1.9% to –42.8%), including 5 (29%) with &gt; -20% regression. Eleven (65%) pts were progression-free for &gt; 24 weeks. Twelve (71%) pts experienced at least one &gt; Grade 3 adverse event related to study treatment. Sixteen pts had at least one treatment interruption or len dose reduction; 2 pts received only 1 cycle of therapy. Five pts were treated beyond first progression without observation of subsequent response. Quality of life data and correlative tissue studies are ongoing. Conclusions: The trial failed to demonstrate that len+pem produces a greater ORR in patients with R/M ACC than what was previously reported with len alone. Further investigation into the biology mediating ICI-resistance and development of novel approaches to augment the efficacy of immune-based therapies in ACC are needed. (Merck Sharp &amp; Dohme LLC, a subsidiary of Merck &amp; Co., Inc., Rahway, NJ, USA provided lenvatinib and pembrolizumab for the study.) Clinical trial information: NCT04209660 .